Cis-6-(acylaminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a, 10b-hexahydro-benzo {8 c{9 -{8 1,6{9 {0 naphthyridine

ABSTRACT

The present invention relates to benzonaphthyridine derivatives of the formula,   WHEREIN R is dichloromethyl, cycloalkyl of 3 to 6 carbon atoms, or alkenyl of 2 to 5 carbon atoms, USEFUL AS BLOOD PLATELET AGGREGATION INHIBITORS.

United States Patent [1 1 ()tt et al.

[ 1 Jan. 21, 1975 CIS-6-(ACYLAMINOPHENYL)-8,9

DIMETHOXY-Z-M ETHYL-1,2,3,4,4A, IOB-HEXAHYDRO-BENZO [C]-[l,6]NAPHTHYRIDINE [75] Inventors: Hans Ott, Pfeffingen; Rudolf Suess,

Bettingen, both of Switzerland [73] Assignee: Sandoz Ltd. a/k/a SandozAG,

Basle, Switzerland [22] Filed: Oct. 18, 1973 211 App]. No.: 407,418

[52] US. Cl..... 260/287 R, 260/283 S, 260/283 SY, 260/286 R, 260/288 R,260/293.85,

OTHER PUBLICATIONS Ott, Chemical Abstracts, Abst. German 2, 123, 328,2-l2-7l, Vol. 76, pg. 381, No. 72495g.

Primary ExaminerDonald G. Daus Assistant ExaminerD. Wheeler Attorney,Agent, or Firm-Gerald D. Sharkin; Robert S. Honor; Thomas O. McGovern[57] ABSTRACT The present invention relates to benzonaphthyridincderivatives of the formula,

NIT-COR wherein R is dichloromethyl, cycloalkyl of 3 to 6 carbon atoms,or alkenyl of 2 to 5 carbon atoms, useful as blood platelet aggregationinhibitors.

7 Claims, No Drawings 1 CIS-6-(ACYLAMINOPHENYL)-8,9DIMETHOXY-2-METHYL-l,2,3,4,4A, IUB-HEXAHYDRO-BENZO [CI-[1,6] NAPHTHYDRIDINEIMPROVEMENTS IN OR RELATlNG TO ORGANIC COMPOUNDS The present inventionrelates to benzonaphthyridine derivatives.

In accordance with the invention there are provided compounds of formulaI,

CHO

Nif-COR wherein R is dichloromethyl, cycloalkyl of 3 to 6 carbon atomsor alkenyl of 2 to carbon atoms.

When the radical R is cycloalkyl of 3 to 6 carbon atoms, this especiallycontains 5 or 6 carbon atoms and may, for example, signify cyclohexyl.

When R is alkenyl of2 to 5 carbon atoms, this radical especiallysignifies vinyl, or vinyl wherein l to 3 hydrogen atoms are substitutedby methyl groups.

The radical R-CONH- is preferably in the 4 position of the phenylradical to which it is bound.

Further. in accordance with the invention, a compound of formula I maybe obtained by a process comprising acylating compounds of formula ll.

II CH O The acylation in accordance with the invention of compounds offormula ll with carboxylic acid halides or anhydrides is convenientlyeffected in an inert organic solvent such as pyridine or acetonitrile.This acyl ation is conveniently effected at a reaction temperaturebetween room temperature and the boiling temperature of the reactionmixture.

The compounds of formula H are known or may be produced in accordancewith known processes or in a manner analogous to known processes.

Acid addition salt forms of compounds of formula I may be produced fromthe free base forms in conventional manner and vice versa. Suitableacids for acid addition salt formation include inorganic acids such ashydrochloric acid, hydrobromic acid, sulphuric acid and organic acidssuch as tartaric acid, benzenesulphonic acid and acetic acid.

In the following non-limitative Examples all temperatures are indicatedin degrees Centigrade and are uncorrected.

EXAMPLE l Cis-6-( 4-dichloroacetylaminophenyl )-8,9 dimethoxy-Z-methyl-l,2,3,4,4a, l Ob-hexahydro-benzo[c][ l ,6]naphthyridine 2 g of6-(4-aminophenyl)-8,9-dimethoxy-2-methyll,2,3,4,4a,lOb-hexahydro-benzo[c][ l,6]naphthyridine. 10 ml of pyridineand 6 g of dichloroacetyl chlo ride are heated to 60 for 2 hours. 10 mlof waterare subsequently added to the reaction mixture and this isevaporated to dryness in a vacuum. The resulting oily residue isdissolved in ethanol and a slight excess of hydrochloric acid in ethanolis added, whereby the title compound crystallizes in dihydrochlorideform as yellowish prisms having a melting point of l07l l 1.

EXAMPLE 2 Cis-6-(4-acryloylaminophenyl )8,9-dimethoxy 2-methyl-l,2,3,4,4a,lOb-hexahydrobenzolc][1,6]naphthyridine The titlecompound is obtained in a manner analogous to that described in ExampleI by acylation of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyll,2,3,4,4a,lOb-hexahydro-benzo[c][1,6]naphthyridinewith acrylic acid chloride. The crude product obtained is worked up byevaporating the mixture to dryness and adding water to the residue. Thereaction mixture is made alkaline with potassium carbonate and extractedwith methylene chloride. The solution is concentrated by evaporation andthe crude product is dissolved in ethanol, hydrochloric acid in ethanolis added to the solution and this is evaporated to dryness in a vacuum.-

Upon adding acetone. the dihydrochloride form of the title compound(melting point 243) crystallizes.

EXAMPLE 3 Cis-6-t 4-cyclohexylcarboxamidophenyl )-8 ,9-dimethoxy-Z-methyl-l ,2,3,4,4a, l Ob-hexahydro-benzo[c][1,6]naphthyridine 3,5 g of6-(4-aminophenyl)-8,9-dimethoxy-2-methyll,2,3,4,4a,l0b-hexahydrobenzo[c][l,6]naphthyridine are dissolved in 40 ml of pyridineand after the addition of 2,3 g of cyclohexylcarboxylic acid chloridethe reaction solution is allowed to stand over night at roomtemperature. After working up and purifying in a manner analogous tothat described in Example 2, the dihydrochloride form of the titlecompound, having a melting point of 236240, is obtained.

The compounds of formula I have not been described in the literature.

The compounds of formula I are useful because they possesspharmacological activity in animals. in particular, the compounds offormula I are useful as blood platelet aggregation inhibitor agents forexample in the treatment and prophylaxis of thrombosis and for improvingmicro-circulation in animals, as indicated by an inhibition of bloodplatelet aggregation induced in vitro by adenosine diphosphate in rabbitplatelet-rich plasma in accordance with the turbidimetric method of Bornat a concentration of from about 20 to about 30 peg/ml of the compounds.

For the above mentioned use the dosage will, of course, vary dependingon the compound employed, mode of administration and therapy desired.However, in general, satisfactory results are obtained when administeredat a daily dosage of from 0.1 mg to about mg per kg animal body weight,conveniently given in divided doses two to four times a day or insustained release form. For the larger mammal, the total daily dosage isin the range from about l0 to about 400mg, and dosage forms suitable fororal administration comprise from about 2 mg to about 200 mg of thecompounds admixed with a solid or liquid pharmaceutical carrier ordiluent.

' The compounds of formula I may be administered in pharmaceuticallyacceptable acid addition salt form. Such acid addition salt formsexhibit the same order of activity as the free base forms and readilyprepared in conventional manner. Representative acids for addition saltformation include organic acids such as maleic, fumaric and tartaricacids and mineral acids such as hydrochloric, hydrobromic anad sulphuricacids. A pharmaceutical composition may comprise a compound of formulaI, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutical carrier or diluent. Suchcompositions conveniently contain more than 1% by weight of the compoundof formula l and may be prepared by conventional techniques to be inconventional forms, for example, capsules, tablets, suppositories,dispersible powders, syrups, elixirs, suspensions or solutions,

. for enteral or parenteral administration. Suitable pharene stearateand polyoxyethylene sorbitan mono-v oleate, granulating anddisintegrating agents such as starch and alginic acid, binding agentssuch as starch, gelatin and acacia, and lubricating agents such asmagnesium stearate, stearic acid and tale, in order to provide anelegant and palatable pharmaceutical preparation. Compositions in tabletform may be coated by Elf-COR wherein R is dichloromethyl, cycloalkyl of3 to 6 carbon atoms or alkenyl of 2 to 5 carbon atoms, or apharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 wherein R is dichloroalkyl.

3. A compound of claim 1 wherein R is cycloalkyl.

4. A compound of claim 1 wherein R is alkenyl.

5. The compound of claim 1, which is Cis-6-( 4'dichloroacetylaminophenyl)-8,9-

dimethoxy-Z-methyl-l,2,3,4,4a,lOb-hexahydrobenzo[c]-[1,6]naphthyridine.

6. The compound of claim I, which is Cis-6-( 4-acryloylaminophenyl)-8,9-dimethoxy2- methyl- 1 ,2,3,4,4a, 1 0b -hexahydro-benzo[c][ l ,6-lnaphthyridine.

7. The compound of claim 1, which isCis-6-(4-cyclohexylcarboxymidophenyl)-8,9-

dimethoxy-Z-methyl-l,2,3,4,4a,IOb-hexahydrobenzo[c]-[1,6]naphthyridine.

2. A compound of claim 1 wherein R is dichloroalkyl.
 3. A compound ofclaim 1 wherein R is cycloalkyl.
 4. A compound of claim 1 wherein R isalkenyl.
 5. The compound of claim 1, which isCis-6-(4-dichloroacetylaminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo(c)-(1,6)naphthyridine.
 6. The compound ofclaim 1, which isCis-6-(4-acryloylaminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a, 10b-hexahydro-benzo(c)(1,6)naphthyridine.
 7. The compound of claim 1, whichis Cis-6-(4-cyclohexylcarboxymidophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo(c)-(1,6)naphthyridine.